Articles https://doi.org/10.1038/s41929-021-00652-8

Copper-catalysed amination of alkyl iodides enabled by halogen-atom transfer

Bartosz Górski1,3, Anne-Laure Barthelemy 1,3, James J. Douglas 2, Fabio Juliá 1 ✉ and Daniele Leonori 1 ✉

Despite the fact that nucleophilic displacement (SN2) of alkyl halides with nitrogen nucleophiles is one of the first reactions introduced in organic chemistry teaching, its practical utilization is largely limited to unhindered (primary) or activated (α-carbonyl, benzylic) substrates. Here, we demonstrate an alternative amination strategy where alkyl iodides are used as radical precursors instead of electrophiles. Use of α-aminoalkyl radicals enables the efficient conversion of the iodides into the corresponding alkyl radical by halogen-atom transfer, while copper catalysis assembles the sp3 C–N bonds at room temperature.

The process provides SN2-like programmability, and application in late-stage functionalization of several densely functionalized pharmaceuticals demonstrates its utility in the preparation of valuable N-alkylated drug analogues.

itrogen-rich molecules form the structural basis of almost species10. The potential of these two elementary steps to assemble a every pharmaceutical and agrochemical lead, as well as broad array of sp3 C–Y bonds (Y = C, N, O, S, halogen) represents a many other high-value products like food additives and powerful opportunity for modular fragment coupling11. N 1 organic materials . A large fraction of these chemotypes contain Despite these prominent features, copper catalysis has seen lim- bonds between nitrogenated residues and saturated carbons, which ited applications to the amination of unactivated alkyl halides12,13. makes the development of methods for sp3 C–N bond construction As shown in Fig. 1c, the overall amination using a [Cu(i)–amido] integral to both academia and industry (Fig. 1a)2–4. species would require initial single-electron transfer (SET) reduc- One classical method is N-alkylation with alkyl (pseudo) tion of the halide, followed by radical capture to give the [alkyl– halides using textbook SN2 (bimolecular nucleophilic substitu- Cu(iii)–amido] complex that undergoes fast reductive elimination. tion) chemistry; however, this reactivity has major limitations in Although radical recombination and reductive elimination are complex molecular settings5. Indeed, while substitutions on pri- very facile, the low reduction potential of unactivated alkyl halides mary substrates are easy to perform, extension to secondary and (Ered < −2 V versus saturated calomel electrode (SCE)) thwarts their tertiary substrates is challenging due to their increased steric hin- activation by Cu(i), ultimately limiting synthetic applications. This drance. The requirement for forcing conditions (strong bases, high lack of reactivity contrasts with the ubiquitous applicability of acti- temperatures) often results in low yields and leads to competitive vated substrates, such as α-carbonyl and benzylic halides14,15, that E2-elimination to alkene by-products. The intrinsic difficulties are much easier to reduce (Ered > −1.5 V versus SCE) and therefore in SN2 reactivity are underscored by the fact that, among all the readily engage in Cu-catalysis. N-nucleophilic substitutions reported in the literature, 93% take In an effort to address this issue, two main approaches have place on primary alkyl halides and only 6% and 1% involve second- emerged in recent years, both relying on the use of photochem- ary and tertiary substrates, respectively (Fig. 1b and Supplementary istry to aid the radical generation step. Fu and Peters reported Fig. 30). Furthermore, the limited pool of substitutions at second- pioneering works using photochemistry to engage unactivated ary centres is largely biased towards the use of activated electro- alkyl and aryl halides in C–N bond formations16–18. In these philes (for example, benzylic, α-carbonyl), making the frequency of examples, photoexcitation of the transient amido–Cu(i) complex nucleophilic displacement at unactivated secondary halides <1.5%. (amido = carbazole, indole, amide) is required to access a highly As a result, the preferred route to assemble C–N bonds on second- reducing species from which SET reduction of the organic halides ary sp3 centres is largely based on the use of ketones via reductive is possible. This strategy, which hinges on the photochemical per- aminations6,7, but this is only feasible for the reaction of alkylamines formance of the amido–Cu(i) complex and is therefore highly and cannot be extended to other valuable N-nucleophiles such as dependent on the N-nucleophile structure, activates the alkyl azoles, amides and carbamates. halide by SET and often requires high-energy UV-light irradia- The limitations of these polar approaches have recently trig- tion (hν = 254 nm)19. gered the exploration of alternative reactivity modes based on radi- An alternative avenue for copper-catalysed aminative cal chemistry. In this context, copper catalysis has demonstrated cross-coupling relies on the combination with visible-light pho- a unique versatility in orchestrating coupling reactions involving toredox catalysis and the use of carboxylic acids or their activated carbon-radical intermediates5,8. The success of these transforma- derivatives as alkyl radical precursors20–22. In these cases, radical tions generally relies on the ability of Cu(ii) complexes to trap car- generation by SET reduction is facile (Ered > −1.5 V versus SCE), bon radicals at near diffusion-controlled rates9, and then undergo but the extension of this approach to unactivated alkyl halides is facile reductive elimination from the resulting high-valent Cu(iii) challenging.

1Department of Chemistry, University of Manchester, Manchester, UK. 2Early Chemical Development, Pharmaceutical Sciences R&D, AstraZeneca, Macclesfield, UK. 3These authors contributed equally: Bartosz Górski, Anne-Laure Barthelemy. ✉e-mail: [email protected]; [email protected]

Nature Catalysis | VOL 4 | July 2021 | 623–630 | www.nature.com/natcatal 623 Articles NaTUre CaTalySiS a OPh

X N S 2 N H N Effective for 1° or N activated 2° alkyl halides NH2 N N O N N N N N N N N HN CN Reductive O Common for alkylamines amination N O but not feasible for N-heteromatics O Imbruvica Xeljanz Kytril Anticancer Immunosuppressant Antiemetic

b c Unactivated 2° alkyl halide (I) (II) 27% [Cu] N [Cu] N (III) I [Cu] N Total frequency of N S 2 reactions N SET Radical Reductive using activation capture elimination N-nucleophiles Challenging Facile Facile Activated 2° alkyl halide 73% ‡ R I R N R Halogen-atom transfer (XAT) R N X X X XAT bypasses challenges in –δ I +δ R redox catalysis R Primary : 93% Secondary : 6% Tertiary: 1% Facile

Fig. 1 | Relevance and assembly of sp3 C–N bonds. a, Molecules containing sp3 C–N bonds are widespread among many high-value materials. However, these bonds are still challenging to assemble. b, Analysis of substitution reactions involving N-nucleophiles and alkyl halides. c, The use of copper catalysis in the amination of unactivated alkyl halides is hampered by the initial SET reduction. Here we demonstrate that XAT using α-aminoalkyl radicals can be used to bypass this issue and enable catalytic sp3 C–N bond formation.

Overall, the limited capacity to access strong reducing species 3-chloroindazole 2. Starting with a Cu(i) catalyst, base-aided azole remains the key element restricting general application of copper coordination is expected to afford the [Cu(i)–2] complex A. At this catalysis in amination chemistry. From this perspective, a strategy stage, we postulated that the known ground-state SET between able to circumvent the problematic alkyl halide SET reduction, Cu(i) and a peroxide B could be used to simultaneously obtain a while still benefitting from the ability of copper to forge sp3 C–N [Cu(ii)–2] complex C and an electrophilic O-radical, D28. This spe- bonds by reductive elimination, might provide a powerful tool cies would have the appropriate philicity and reactivity profile to towards achieving the assembly of complex nitrogenated motifs. undergo HAT selectively at the α-N position of alkyl amine E29. The Recently, ourselves23,24 and the group of Doyle25,26 have demon- activated nature (bond-dissociation energy (BDE) = 91 kcal mol−1)30 strated that alkyl radicals can be accessed from the corresponding and hydridic character of this C–H bond should lead to a halides by exploiting the ability of α-aminoalkyl radicals to trigger polarity-matched process resulting in the α-aminoalkyl radical F. halogen-atom-transfer (XAT) reactions. This blueprint for radical This species is the key agent for the homolytic activation of iodide 1 generation is facilitated by the interplay of strong polar effects in through XAT and would generate the alkyl radical G (and iminium the transition state of the halide abstraction step27 and can be used H). At this point, fast capture of radical G by C would provide the as part of C–C bond-forming strategies such as Giese alkylation high-valent [alkyl–Cu(iii)–2] species I from which reductive elimi- and Heck-type olefination. We recently questioned if this reactivity nation is facile. This last step would forge the targeted sp3 C–N bond mode could be integrated with copper catalysis to enable sp3 C–N in 3 and regenerate the Cu(i) catalyst. bond formation. Such a strategy would benefit from a carbon–halo- The realization of this approach is not without challenges, gen bond-activation step occurring outside the copper cycle, inde- as it requires the synchronized interplay of SET → HAT → XAT pendently from the nature of the N-nucleophile and also obviating steps. Indeed, examination of this mechanistic pathway revealed for the need for additional photocatalysis. three major aspects potentially hampering reactivity. Because In this Article, we describe the successful realization of this pro- α-aminoalkyl radicals are electron-rich species (Eox ≈ −1.1 V versus posal and demonstrate that integration of α-aminoalkyl-mediated SCE)29, XAT needs to be faster than both oxidation of F by peroxide XAT with copper catalysis is a practical and effective tool to achieve B (leading to H) and also capture of F by the Cu(ii) species C, which the amination of secondary alkyl iodides. This mode for sp3 C–N would result in aminal-type by-products (Supplementary Figs. 27 bond formation is fast, operates under mild conditions, display and 28). Furthermore, radical capture of alkyl radical G by C needs broad functional group tolerance and can be used in the late-stage to outcompete a potential H-abstraction from amine E, which functionalization of complex bioactive materials. would result in dehalogenation (Supplementary Fig. 29). With this mechanistic picture in mind, the model reaction Results between iodide 1 and azole 2 was evaluated. After screening of Reaction design and optimization. A detailed description of the reaction conditions, we identified an effective protocol leading to reaction design for this XAT–Cu-mediated amination is provided the formation of 3 in high yield in just 1 h at room temperature in Fig. 2a using the coupling of 4-iodo-N-Boc-piperidine 1 with (Fig. 2b). This process uses [Cu(CH3CN)4]PF6 as the catalyst, n-Bu3N

624 Nature Catalysis | VOL 4 | July 2021 | 623–630 | www.nature.com/natcatal NaTUre CaTalySiS Articles

a H Cl n n Pr N( Bu)2 N O E Ph O TMS Base-H (I) N B [LnCu] A HAT Cl SET Ph O Ph OH D Base + N N Cl H 2 (I) N Cu-catalyzed radical XAT with nPr N(nBu) [LnCu] 2 amination (II) N α-aminoalkyl radicals F [LnCu] C

Cl I Cl XAT N N N N Boc Boc N (III) N G 1 [LnCu] N Boc 3 n n – Pr N( Bu)2 I N H Boc I

b Cl cumOOTMS (4.0 equiv.) H Cl N H Cu(CH CN) PF (10 mol%) I 3 4 6 EtO C CO Et n N 2 2 + ( Bu)3N (5.0 equiv.), BTMG (2.0 equiv.) N N N Boc H CH CN–t BuOH (1:1, 0.1 M), r.t., 1 h N N 3 Boc H 1 2 (1.0 equiv.) (1.5 equiv.) 3 4 5

Entry Variations Yield (%) Entry Variations Yield (%) Entry Variations Yield (%) n 1 None 74 5 No BTMG – 9 (Me3Si)3SiH instead of ( Bu)3N 20 n 2 No [Cu(MeCN)4]PF6 – 6 Et3N instead of ( Bu)3N 68 10 Reaction on 20 mmol 59 n 3 No cumOOTMS – 7 DABCO instead of ( Bu)3N – 11 Additive = 4 (5.0 equiv.) – n 4 No ( Bu)3N – 8 T = 0 °C instead of r.t. 70 12 Additive = 5 (5.0 equiv.) –

c 2.0

iv 1 ii iii v 1.5 No changes Cl ii N 2 i iv Cl 1.0 Cu(CH3CN)4PF6 (I) N BTMG [LnCu] N i

A Absorbance (a.u.) B (II) N 0.5 iii [LnCu] C

v 0 250 350 450 550 650 750 Cl Cl Wavelength (nm) d O N N O + O 10 t N 10 (II) N CH3CN– BuOH (1:1, 0.1 M) O [LnCu] 80 °C, 1 h 9 65% 7 6 C (5.0 equiv.) (1.0 equiv.)

Fig. 2 | Development of a coupling between alkyl iodides and N-nucleophiles by merging XAT and copper catalysis. a, The proposed mechanism for the amination of secondary alkyl iodides requires the merging of copper catalysis and XAT reactivity. b, Optimization of the amination process between iodide 1 and N-nucleophile 2 and relevant control reactions. c, UV–vis absorption spectroscopy studies support the individual steps in the catalytic cycle. d, Experiments probing the ability of alkyl radicals to undergo amination by reacting with [Cu(ii)–N-nucleophile] species. as the α-aminoalkyl radical precursor, trimethylsilyl (TMS)-protected discussed in the Supplementary Methods, but some experiments cumyl peroxide (cumOOTMS) as the oxidant and BTMG were of high relevance. Control reactions demonstrated that all com- (2-tert-butyl-1,1,3,3-tetramethylguanidine) as the base (pKa = 26.5) ponents (copper catalyst, amine, oxidant and base) were required in CH3CN–t-BuOH solvent. Full details on the optimization are to obtain the product (entries 2–5, Fig. 2b). Although n-Bu3N

Nature Catalysis | VOL 4 | July 2021 | 623–630 | www.nature.com/natcatal 625 Articles NaTUre CaTalySiS

cumOOTMS (4.0 equiv.)

I [Cu(MeCN)4]PF6 (10 mol%) N n + N Bu3N (5.0 equiv.), BTMG (2.0 equiv.) N H N Boc t Boc CH3CN– BuOH (1:1)(0.1 M), r.t.,1 h 1 (1.5 equiv.) 3, 8–38 (1.0 equiv.)

Cl Br CO2Me

N N N N N N N N N N

N N N N N Boc Boc Boc Boc Boc 3 8 9 10 11 74% 36% 50%a 75% 80%b,c CO2Me

NHBoc

N N N OMe N F N

N N N N N Boc Boc Boc Boc Boc 12 13 14 15 16 64% 75%b 84%b 73%b 73%

CONH2

N H N N N N N N N N N N N N Boc Boc Boc Boc Cl Boc 17 18 19 20 21 44%a 72% 41%a,c 51%b 72%

H H H H H N N N N N N N N N N

N N N N N Boc Br Boc Boc Boc Boc CF3 22 OMe 23 F 24 25 26 78%c 80%a 66%b,c 58% 42%b,c

Ph H H H H N N N N N N N N N N

N N N N N N N Boc Br Cl Boc Boc Boc Boc I 27 28 29 30 31 61%b,c 46%a,c 48% 77% 47%b,c,d

H H H N N Ph N N N N Ph NH2 N PPTS N N N N N N N Ph N Boc Boc N Boc Boc Boc 32 33 34 35 36 51%b,c 43%b,c 73%b 52% Quant.

O O O H H N N N Ph N Ph Unsuccessful N N N-nucleophiles: N O N Boc Boc Boc Boc 37 38 39 40 62% 98%b – –

Fig. 3 | Scope of the N-nucleophilic partner for the amination of iodide 1. Notes: areaction performed using CuI as the [Cu(i)] catalyst; breaction performed c d using CuCl as the [Cu(i)] catalyst; reaction performed at 0 °C; reaction performed using DMF–CH3CN (9:1) as the solvent. Boc, t-butyloxycarbonyl. provided the highest reaction yield, other amines were compat- frequently adopted as XAT reagent in both classical radical chem- ible as long as they led to the generation of an α-aminoalkyl radical istry as well as modern photoredox-based approaches34, resulted in (entries 6 and 7). The coupling was also efficient at 0 °C (entry 8), low yields owing to competitive dehalogenation (entry 9). which is in contrast with the high temperatures (T > 100 °C) gen- In terms of reproducibility and scalability, the process was insen- erally required in processes based on Cu/peroxide systems for sp3 sitive to the presence of water and was run in the laboratory of C–H functionalization31,32. Finally, the use of supersilane33, which is AstraZeneca up to multi-gram scale (20 mmol), providing similar

626 Nature Catalysis | VOL 4 | July 2021 | 623–630 | www.nature.com/natcatal NaTUre CaTalySiS Articles

Cl cumOOTMS (4.0 equiv.) Cl [Cu(MeCN)4]PF6 (10 mol%) N n I Bu3N (5.0equiv.), BTMG (2.0 equiv.) N + N N CH CN–tBuOH (1:1) (0.1 M), r.t., 1 h H 3 2 41–60 (1.0 equiv.) (1.5 equiv.)

Cl Cl Cl Cl Cl

N N N N N N N N N Ph N O F Ph F 41 42 43 O 44 45 80% 62%a 66% 96%b,c 37%a

Cl Cl Cl Cl Cl

N N N N N N N N N N

N O N O S Boc N 50 Boc 46 47 48 49 44%a 63%a 86%a 84%a 91%

I Cl Cl Cl Cl Cl

N N N N N N N N N N

O N BocHN MeO2C Boc N 51 52 Boc 53 54 55 92% 76%a 50%d 93%a 52%

Boc N Cl Cl Cl Cl

N H OEt N F N N N N N N H H N N O 56 57 58 59 60 a,c O 74% e 41%, d.r. 6.8:1 a a Cl 31% 46%, d.r. 5.1:1 61%

Fig. 4 | Scope of the secondary alkyl iodide partner for the amination with N-nucleophile 2. Notes: areaction performed using CuCl as the [Cu(i)] catalyst; breaction performed using CuI as the [Cu(i)] catalyst; creaction performed at 0 °C; dreaction performed using CuI (1 mol%) as the [Cu(i)] catalyst; ereaction performed using CF3–C6H5:CH3CN (9:1) as the solvent. Boc, t-butyloxycarbonyl; d.r., diastereomeric ratio. yields of 3 (entry 10). Peroxides are often problematic reagents due Next, we sought to use UV–vis absorption spectroscopy to to their potentially exothermic decomposition. Before scale-up, obtain further information on some of the individual steps involved safety assessments performed at AstraZeneca demonstrated that in the copper catalytic cycle (Fig. 2c). When a colourless solution of cumOOTMS can be handled safely and does not have explosive [Cu(MeCN)4]PF6 was treated with 2 in the presence of BTMG, a pale properties (differential scanning calorimetry analysis showed an exo- yellow solution was formed. The formation of [Cu(i)–2] A was pos- therm at T > 107 °C), thus alleviating the initial concerns associated sible only in the presence of the base, as also confirmed by 1H NMR with the scale-up of this methodology (Supplementary Methods). spectroscopy (Supplementary Fig. 13). The addition of alkyl iodide 1 to this solution did not lead to any significant change in the UV–vis Mechanistic studies. Under our reaction conditions, α-aminoalkyl spectrum, and the foreseen lack of reactivity between A and 1 was radical F is generated by HAT on n-Bu3N. The inclusion of addi- also demonstrated by stoichiometric experiments (Supplementary tives with weaker and hydridic C–H bonds should therefore inter- Figs. 14 and 15). By contrast, addition of cumOOTMS resulted in fere with this step and, by outperforming the amine in the reaction an immediate colour change to dark green, which corresponded with D, suppress the coupling process31. Indeed, when 5.0 equiv. to the appearance of a new absorbance band centred at ~600 nm, −1 35 37,38 of 9,10-dihydroanthracene 4 (BDEC–H = 76 kcal mol ) or the matching those reported for other amido–[Cu(ii)] complexes . −1 36 Hantzsch ester 5 (BDEC–H = 69 kcal mol ) were incorporated, no This supports the formation of [Cu(ii)–2] C, as further confirmed product was detected and the alkyl iodide was largely recovered by comparison with a sample of [Cu(ii)–2] complex (obtained by (Fig. 2b, entries 11 and 12). Together with the lack of reactivity mixing Cu(OTf)2 + 2 + BTMG) (Supplementary Figs. 14 and 15). observed when amines without α-N C–H bonds were employed (for Finally, to validate the last step of the copper catalytic cycle, we example 1,4-diazabocyclo[2.2.2]octane, DABCO) (Supplementary studied the stoichiometric reaction of C with alkyl radicals gener- Information), these competition experiments prove the fundamen- ated by thermal decomposition of lauroyl peroxide 6. As shown in tal role of F in the C–I bond-activation step. Fig. 2d, the successful formation of 7 provides evidence supporting

Nature Catalysis | VOL 4 | July 2021 | 623–630 | www.nature.com/natcatal 627 Articles NaTUre CaTalySiS

Ac H N N O N MeO H O O O N N Boc O F O N N O N F N Ph N N From melatonin From metaxalone From fenspiride From zolmitriptan Boc Boc Sleep hormone Muscle relaxant Antitussive Treatment of migraine 61 62 63 64 99%a 98%a 71% 57%b

Boc O O N N NH N HN O MeO N N H O N O Boc N OH N N CO2Me O N H H N N MeO N N O H O H OMe S From imiquimod From trimethoprim From lamivudine From Boc-Gly-Leu-Trp-OMe Treatment of carcinoma Antibiotic Antiretroviral Tripeptide 65 66 67 68 98%a,c 44%a,d 52% 22%

Fig. 5 | Late-stage N-alkylations of complex and biologically active materials. Notes: areaction performed using CuCl as the [Cu(i)] catalyst; breaction c d performed using CuI as the [Cu(i)] catalyst; reaction performed using DMF:t-BuOH (9:1) as the solvent; reaction performed using DMF:CH3CN (9:1) as the solvent. Boc, t-butyloxycarbonyl.

the proposed radical metallation on [Cu(ii)–2], followed by reduc- to rule out background SN2 reactivity (Supplementary Tables 2, 5, tive elimination that complete our proposed mechanism for sp3 6 and 7). In all cases, no product formation was detected when the C–N bond assembly31. reactions were run in the absence of copper catalyst and oxidant. Our scope evaluation demonstrated wide compatibility with many

Substrate scope. The optimized reaction conditions were then classes of N-reagents, notoriously difficult in classical SN2 settings. In applied to a wide variety of N-nucleophiles using 1 as the coupling terms of limitations, we did not succeed in extending this chemistry partner (Fig. 3). The N-alkylation of azoles is still a recognized chal- to less nucleophilic benzamide (for example, 39) and aniline (40). lenge in synthetic chemistry, so we were pleased to see that many UV–vis absorption spectroscopy studies were therefore conducted to systems were compatible with our process. This included differ- understand and identify the recalcitrant step in the copper catalytic entially substituted indazoles (8–11) and indoles (12–15), which cycle that was thwarting reactivity. In general, coordination of the could incorporate handles for further cross-coupling, such as chlo- N-nucleophile to Cu(i) and/or the oxidation of the resulting species ride, bromide and ester functionality. Pleasingly, we succeeded in are currently believed to be the limiting steps, potentially resulting in alkylating a protected tryptophan residue (16) and also accessed 17, unproductive pathways for the alkyl iodide, such as dehalogenation which is a synthetic intermediate for the preparation of the antineo- or elimination (Supplementary Figs. 22–26). This lack of reactivity plastic enzastaurin39. Carbazole (18) and pyrrole (19) could be used, has, however, provided a substantial opportunity for the chemose- as well as a functionalized 7-deazapurine (20), which is a common lective alkylation of complex materials (see below) that would have scaffold in many blockbuster drugs like pevonedistat (anticancer). been very challenging using ionic approaches. Aminopyridines are motifs frequently encountered in The alkyl iodide scope was evaluated using 2 as the nucleo- drug-development campaigns and could also be alkylated in high phile, and our conditions proved general for a broad array of sub- yields. Electronic (21–26) and steric (27) perturbation of the system strates (Fig. 4a). Both cyclic and acyclic systems were successfully did not hamper reactivity, and we also succeeded in using the less engaged, as demonstrated by the formation of 41–45, which also nucleophilic N-phenyl derivative (28). Other systems that under- contain HAT-activated benzylic and α-O positions. Several hetero- went efficient coupling with 1 were 2-aminoquinoline (29), several cyclic building blocks were evaluated and this included protected 2-amino-pyrimidines (30–32), 2-amino-pyrazine (33), as well as 3- and 4-iodo-piperidines (46 and 47), which increased the number 2-aminopyrrolo[2,1-f][1,2,4]triazine (34), which is found in the of functionalities tolerated. Notably, the chemoselective activation structure of many commercial drugs, including remdesivir, an anti- of alkyl versus aryl iodides is demonstrated in 47, which would be viral considered for the treatment of COVID-19 infections40. difficult by other strategies based on either SET or metal-mediated We then considered the possibility of using this chemistry to oxidative addition. This method also enabled coupling of 2 with convert alkyl iodides into primary amines, something challenging 4-iodo(thio)pyranes (48 and 49), 2-iodo-N-Boc-azetidine (50) with ammonia owing to known over-alkylation issues. Pleasingly, and 2-iodo-oxetane (51). Spirocyclic fragments43 are now popular we could engage commercially available benzophenoneimine41,42 as in medicinal chemistry campaigns to increase the sp3 content in an effective surrogate providing 35, which, upon simple deprotec- organic leads44, and our methodology successfully led to the for- tion, gave primary amine 36. mation of 52 and 53 in good yield, while 3-substitued cyclobutyl The use of carbamates/amides in this coupling process proved iodides gave 54 and 55. difficult (see below), but we nonetheless demonstrate efficient alkyl- The majority of alkyl iodides used in the scope are commercial ation of a cyclic carbamate (37), as well as a β-lactam that gave 38 in building blocks. However, a powerful application was found by the near quantitative yield. preparation of nitrogenated scaffolds exploiting secondary alcohols The Supplementary Discussion contains information regarding via the Appel reaction and several olefins after iodo-functionalizations. additional control experiments run with each class of nucleophiles For example, hydroxyl group-containing alkaloid nortropine and

628 Nature Catalysis | VOL 4 | July 2021 | 623–630 | www.nature.com/natcatal NaTUre CaTalySiS Articles

3α-cholestane were used to obtain indazole products 56 and 57 as sin- References gle diastereomers. Furthermore, iodo-etherification and -fluorination 1. Ricci, A. Amino Group Chemistry: From Synthesis to the Life Sciences of cyclohexene enabled formation of valuable vicinal ether and F (Wiley-VCH, (2008). 2. Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, derivatives 58 and 59, while iodolactonization then amination of substitution patterns, and frequency of nitrogen heterocycles among U.S. norbornene carboxylic acid gave 60 in good yield. In all cases, the FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014). diasteroselectivity of the initial iodo-functionalization was inconse- 3. Brown, D. G. & Boström, J. Analysis of past and present synthetic quential, as the substrates underwent stereoconvergent amination methodologies on medicinal chemistry: where have all the new reactions at the less hindered side. Hence, olefin iodo-functionalization rep- gone? J. Med. Chem. 59, 4443–4458 (2016). 4. Trowbridge, A., Walton, S. M. & Gaunt, M. J. New strategies for the resents a powerful gateway to quickly enlarge the pool of substrates transition-metal catalyzed synthesis of aliphatic amines. Chem. Rev. 120, available to this aminative coupling that cannot be accessed using, for 2613–2692 (2020). example, radical strategies based on activated carboxylic acids. 5. Kaga, A. & Chiba, S. Engaging radicals in transition metal-catalyzed Figure 5 depicts several examples of how this reaction can be cross-coupling with alkyl electrophiles: recent advances. ACS Catal. 7, applied at a late stage for the N-alkylation of many complex bio- 4697–4706 (2017). 6. Afanasyev, O. I., Kuchuk, E., Usanov, D. L. & Chusov, D. Reductive amination active materials. We succeeded in the selective and high-yielding in the synthesis of pharmaceuticals. Chem. Rev. 119, 11857–11911 (2019). alkylation of the indole ring in the sleep hormone melatonin in the 7. Kumar, R., Flodén, N. J., Whitehurst, W. G. & Gaunt, M. J. A general presence of a tethered N-acetamide group (61). The oxazolidinone carbonyl alkylative amination for tertiary amine synthesis. Nature 581, ring in metaxalone (62, a widely used muscle relaxant) and the anti- 415–420 (2020). tussive fenspiride (63) were alkylated in high yield. The successful 8. Hossain, A., Bhattacharyya, A. & Reiser, O. Copper’s rapid ascent in visible-light photoredox catalysis. Science 364, eaav9713 (2019). formation of 63 also demonstrates compatibility with tertiary amine 9. Kochi, J. K. & Subramanian, R. V. Kinetics of electron-transfer oxidation of functionalities, which are often problematic in photoredox cataly- alkyl radicals by copper(ii) complexes. J. Am. Chem. Soc. 87, 4855–4866 (1965). sis. The migraine treatment medicine zolmitriptan is an interesting 10. Casitas, A. & Ribas, X. Te role of organometallic copper(iii) complexes in example because of the presence of both free indole and oxazolidi- homogeneous catalysis. Chem. Sci. 4, 2301–2318 (2013). none. Our reaction conditions enabled a complete discrimination 11. Zhu, X. & Chiba, S. Copper-catalyzed oxidative carbon–heteroatom bond formation: a recent update. Chem. Soc. Rev. 45, 4504–4523 (2016). between these two nucleophilic sites, resulting in the chemoselec- 12. Jacobson, R. R., Tyeklár, Z. & Karlin, K. D. Reaction of organic halides with tive alkylation of the azole framework (64). [CuI(TMPA)CH3CN]PF6. Inorg. Chim. Acta 181, 111–118 (1991). We then applied the method to the alkylation of complex 13. Cheng, L.-J. & Mankad, N. P. C–C and C–X coupling reactions of 2-aminopyridine- and 2-amino-pyridimidine-based drugs imiqui- unactivated alkyl electrophiles using copper catalysis. Chem. Soc. Rev. 49, mod and trimethoprim, which gave 65 and 66 in good to excellent 8036–8064 (2020). 14. Matsumoto, Y. et al. Amino acid Schif base bearing benzophenone imine as yield. In the latter case, double alkylation of both nucleophilic NH 2 a platform for highly congested unnatural α-amino acid synthesis. J. Am. groups was possible by increasing the equivalents of 4-iodopirane. Chem. Soc. 142, 8498–8505 (2020). Another example of chemoselective N-alkylation is provided by 15. Ishida, S., Takeuchi, K., Taniyama, N., Sunada, Y. & Nishikata, T. the formation of 67 from the antiretroviral lamivudine. The suc- Copper-catalyzed amination of congested and functionalized cess of this example is remarkable, as reactivity was exclusive at the α-bromocarboxamides with either amines or ammonia at room temperature. Angew. Chem. Int. Ed. 56, 11610–11614 (2017). 4-aminopyridinone core in the presence of a primary alcohol, two 16. Bissember, A. C., Lundgren, R. J., Creutz, S. E., Peters, J. C. & Fu, G. C. activated positions for HAT and a thioether. Finally, we obtained Transition-metal-catalyzed alkylations of amines with alkyl halides: preliminary results demonstrating applicability of the coupling pro- photoinduced, copper-catalyzed couplings of carbazoles. Angew. Chem. Int. cess in the alkylation of tryptophan residues in small peptides (68). Ed. 52, 5129–5133 (2013). 17. Kainz, Q. M. et al. Asymmetric copper-catalyzed C–N cross-couplings induced by visible light. Science 351, 681–684 (2016). Conclusions 18. Creutz, S. E., Lotito, K. J., Fu, G. C. & Peters, J. C. Photoinduced Ullmann In summary, the integration of α-aminoalkyl radical-mediated XAT C–N coupling: demonstrating the viability of a radical pathway. Science 338, with copper catalysis has led to the development of an efficient strat- 647–651 (2012). egy for the coupling of secondary alkyl iodides with N-nucleophiles. 19. Do, H.-Q., Bachman, S., Bissember, A. C., Peters, J. C. & Fu, G. C. The utilization of this strategy eliminates the requirement for strong Photoinduced, copper-catalyzed alkylation of amides with unactivated secondary alkyl halides at room temperature. J. Am. Chem. Soc. 136, reductants in the alkyl radical generation step. This reactivity occurs 2162–2167 (2014). at room temperature under just 1 h and enables the preparation of 20. Mao, R., Frey, A., Balon, J. & Hu, X. Decarboxylative C(sp3)–N cross-coupling many complex building blocks that are elusive through SN2 reactivity. via synergetic photoredox and copper catalysis. Nat. Catal. 1, 120–126 (2018). 21. Liang, Y., Zhang, X. & MacMillan, D. W. C. Decarboxylative sp3 C–N Methods coupling via dual copper and photoredox catalysis. Nature 559, 83–88 (2018). General procedure for the amination of alkyl iodides. An oven-dry tube 22. Nguyen, V. T. et al. Visible-light-enabled direct decarboxylative N-alkylation. equipped with a stirring bar was charged with the alkyl iodide (0.20 mmol, Angew. Chem. Int. Ed. 59, 7921–7927 (2020). 23. Constantin, T. et al. Aminoalkyl radicals as halogen-atom transfer agents for 1.0 equiv.), the N-nucleophile (0.30 mmol, 1.5 equiv.) and [Cu(MeCN)4]PF6 (7.5 mg, 0.020 mmol, 10 mol%). Te tube was capped with a Supelco aluminium activation of alkyl and aryl halides. Science 367, 1021–1026 (2020). 24. Constantin, T. et al. A case of chain propagation: α-aminoalkyl radicals as crimp seal with septum (PTFE/butyl) and evacuated and reflled with N2 (three initiators for aryl radical chemistry. Chem. Sci. 11, 12822–12828 (2020). times). Dry and degassed CH3CN (1.0 ml), t-BuOH (1.0 ml), (n-Bu)3N (238 μl, 1.0 mmol, 5.0 equiv.), BTMG (80 μl, 0.40 mmol, 2.0 equiv.) were sequentially 25. Nef, R. K. et al. Generation of halomethyl radicals by halogen atom added. Te resulting solution was treated with cumOOTMS (224 mg, 238 μl, abstraction and their addition reactions with alkenes. J. Am. Chem. Soc. 141, 1.00 mmol, 5.0 equiv.) dropwise under vigorous stirring. Afer 1 h the tube was 16643–16650 (2019). opened and the mixture diluted with brine (2 ml) and EtOAc (2 ml). Te organic 26. Su, Y. L. et al. α-Amino radical-mediated diverse difunctionalization of layer was separated and the aqueous layer was extracted with EtOAc (5 ml × 2). Te alkenes: construction of C−C, C−N and C−S bonds. ACS Catal. 10, 13682–13687 (2020). combined organic layers were dried (MgSO4), fltered and evaporated. Te crude material was purifed by fash column chromatography on silica gel. 27. Tedder, J. M. Te importance of polarity, bond strength and steric efects in determining the site of attack and the rate of free radical substitution in aliphatic compounds. Tetrahedron 38, 313–329 (1982). Data availability 28. Kharasch, M. S. & Sosnovsky, G. Te reactions of t-butyl perbenzoate and The data supporting the findings of this study are available within the paper and its olefns—a stereospecifc reaction. J. Am. Chem. Soc. 80, 756–756 (1958). Supplementary Information or from the authors upon reasonable request. 29. Wayner, D. D. M., Dannenberg, J. J. & Griller, D. Oxidation potentials of α-aminoalkyl radicals: bond dissociation energies for related radical cations. Received: 11 January 2021; Accepted: 11 June 2021; Chem. Phys. Lett. 131, 189–191 (1986). 30. Lalevée, J., Allonas, X. & Fouassier, J.-P. N−H and α(C−H) bond dissociation Published online: 12 July 2021 enthalpies of aliphatic amines. J. Am. Chem. Soc. 124, 9613–9621 (2002).

Nature Catalysis | VOL 4 | July 2021 | 623–630 | www.nature.com/natcatal 629 Articles NaTUre CaTalySiS

31. Tran, B. L., Li, B., Driess, M. & Hartwig, J. F. Copper-catalyzed intermolecular 43. Carreira, E. M. & Fessard, T. C. Four-membered ring-containing amidation and imidation of unactivated alkanes. J. Am. Chem. Soc. 136, spirocycles: synthetic strategies and opportunities. Chem. Rev. 114, 2555–2563 (2014). 8257–8322 (2014). 32. Wang, C.-S., Wu, X.-F., Dixneuf, P. H. & Soulé, J.-F. Copper-catalyzed 44. Lovering, F., Bikker, J. & Humblet, C. Escape from Flatland: increasing oxidative dehydrogenative C(sp3)−H bond amination of (cyclo)alkanes using saturation as an approach to improving clinical success. J. Med. Chem. 52, NH-heterocycles as amine sources. ChemSusChem 10, 3075–3082 (2017). 6752–6756 (2009). 33. Chatgilialoglu, C., Ferreri, C., Landais, Y. & Timokhin, V. I. Tirty years of (TMS)3SiH: a milestone in radical-based synthetic chemistry. Chem. Rev. 118, Acknowledgements 6516–6572 (2018). D.L. thanks EPSRC for a fellowship (EP/P004997/1) and a research grant (EP/ 34. Zhang, P., Le, C. C. & MacMillan, D. W. C. Silyl radical activation of alkyl T016019/1) and the European Research Council for a research grant (758427). We thank halides in metallaphotoredox catalysis: a unique pathway for W. Ashworth, P. Gillespie and S. Wells for performing safety studies. We thank cross-electrophile coupling. J. Am. Chem. Soc. 138, 8084–8087 (2016). M. Johansson (AstraZeneca) for useful discussions. 35. Stein, S. E. & Brown, R. L. Prediction of carbon–hydrogen bond dissociation energies for polycyclic aromatic hydrocarbons of arbitrary size. J. Am. Chem. Soc. 113, 787–793 (1991). Author contributions 36. Zhu, X.-Q. et al. Determination of the C4–H bond dissociation energies of F.J. and D.L. designed the project and directed the work. B.G. and A.-L.B. performed all NADH models and their radical cations in acetonitrile. Chem. Eur. J. 9, the synthetic and mechanistic experiments. J.J.D performed the scale-up experiments. 871–880 (2003). All authors analysed the results and wrote the manuscript. 37. Wiese, S. et al. Catalytic C–H amination with unactivated amines through copper(ii) amides. Angew. Chem. Int. Ed. 49, 8850–8855 (2010). Competing interests 38. Ahn, J. M., Ratani, T. S., Hannoun, K. I., Fu, G. C. & Peters, J. C. The authors declare no competing interests. Photoinduced, copper-catalyzed alkylation of amines: a mechanistic study of the cross-coupling of carbazole with alkyl bromides. J. Am. Chem. Soc. 139, 12716–12723 (2017). Additional information 39. Wang, M. et al. [11C]enzastaurin, the frst design and radiosynthesis of a new Supplementary information The online version contains supplementary material potential PET agent for imaging of protein kinase C. Bioorg. Med. Chem. Lett. available at https://doi.org/10.1038/s41929-021-00652-8. 21, 1649–1653 (2011). 40. Wang, Y. et al. Remdesivir in adults with severe COVID-19: a randomised, Correspondence and requests for materials should be addressed to F.J. or D.L. double-blind, placebo-controlled, multicentre trial. Lancet 395, Peer review information Nature Catalysis thanks Michael Doyle and 1569–1578 (2020). the other, anonymous, reviewer(s) for their contribution to the peer review 41. Mao, R., Balon, J. & Hu, X. Cross-coupling of alkyl redox-active esters with of this work. benzophenone imines: tandem photoredox and copper catalysis. Angew. Reprints and permissions information is available at www.nature.com/reprints. Chem. Int. Ed. 57, 9501–9504 (2018). 42. Peacock, D. M., Roos, C. B. & Hartwig, J. F. Palladium-catalyzed cross Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in coupling of secondary and tertiary alkyl bromides with a nitrogen published maps and institutional affiliations. nucleophile. ACS Cent. Sci 2, 647–652 (2016). © The Author(s), under exclusive licence to Springer Nature Limited 2021

630 Nature Catalysis | VOL 4 | July 2021 | 623–630 | www.nature.com/natcatal